The VHL gene was first identified in 1993 as the gene responsible for a rare inherited cancer syndrome called Von Hippel-Lindau disease. Inheritance of a single defective VHL gene results in the predisposition to the development of a variety of cancers including clear cell renal carcinoma, pheochromocytoma, and angioblastomas of the central nervous system, among others. Subsequently, it was shown that the majority of tumors derived from patients with sporadic clear cell renal carcinoma also contained both loss of heterozygosity of the VHL locus and failure of expression and/or mutations in the remaining VHL allele. The goal of this project is to understand the biochemistry and cell biology of the VHL gene product and thereby to elucidate its role in cell transformation. Studies over the past year include the completion of the cloning and sequencing of the human and rat VHL gene, the biochemical characterization of the gene product and its intracellular localization. The identification and cloning of gene products that VHL interacts with has illuminated an unexpected new area of gene control--the regulation of transcriptional elongation.